An overexpression and increase have been observed in the concentration and activity of the ubiquitin‐specific protease 21 (USP21) enzyme in many cancers, necessitating the need for the development of new inhibitor drugs against the same. The current study attempts to discover one such novel potential inhibitor of USP21 by the application of various bioinformatics techniques which include molecular modeling, pharmacophore mapping, pharmacophore‐based virtual screening, molecular docking, and ADMET prediction followed by molecular dynamics simulations. Following this inverted funnel‐like approach, we finally ended up with one ligand–ZINC02422616 which displays a very high binding affinity toward the USP21 domain. This ligand contains all the pharmacophoric features displayed by the compounds that are potential inhibitors of the USP21 domain. Moreover, it shows a favorable pharmacokinetic, pharmacodynamic, and ADMET profile, along with strong hydrophobic interaction and hydrogen bonding with the domain. Simulation studies showed that the complex remains stable over time, with the bound protein displaying a more constrained motion in the conformational space compared to the unbound form. The ligand showed a highly favorable free energy landscape/surface, forming several energy minima's in contrast to the unbound domain in which most conformations occupied a relatively higher energy state. Moreover, the ligand also displayed a Kd of 422.8 nM and a free energy of binding ΔG of −8.6 kcal/mol, both of which indicate a very high affinity toward the target domain. This potential drug candidate can then be used as a viable treatment method for many types of cancers caused by USP21.

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Background: Interleukin-11 is a pleiotropic cytokine that is known to play an important role in the progression of various forms of cancer by modulating the survival and proliferation of tumour cells. IL11 also demonstrates a structural homology to IL6 - the predominant cytokine involved in COVID-19. This makes IL11 a potential therapeutic target in both diseases. Objective: This study aimed to evaluate the impact of the two point mutations- R135E and R190E on the stability of IL11 and their effect on the binding affinity of IL11 with its receptor IL11Rα. It is a molecular level analysis based on the existing experimental validation. Method: Computer-aided drug designing techniques such as molecular modelling, molecular docking, and molecular dynamics simulations were employed to determine the consequential effects of the two point mutations. Results: Our analysis revealed that the two mutations led to a decrease in the overall stability of IL11. This was evident by the increased atomic fluctuations in the mutated regions as well as the corresponding elevation in the deviations seen through RMSD and Rg values. It was also accompanied by a loss in the secondary structural organisation in the mutated proteins. Moreover, mutation R135E led to an increase in the binding affinity of IL11 with IL11Rα and the formation of a more stable complex in comparison to the wild-type protein with its receptor. CONCLUSION: Mutation R190E led to the formation of a less stable complex than the wild-type which suggests a decrease in the binding affinity between IL11 and IL11Rα.